Procedure for producing formyl imidazoles

ABSTRACT

A new procedure for the catalytic conversion of hydroxy methyl imidazoles to formyl imidazoles is described. The catalysis takes place in the presence of a peroxide. Formyl imidazoles are important intermediate products for pharmaceutical substances.

This application is a 371 of PCT/EP99/04107 Jun. 11, 1999.

SPECIFICATION

This invention concerns a new procedure for producing formyl imidazolesof the general formula

in which R¹ means an alkyl group, by catalytic oxidation of hydroxymethyl imidazoles of the general formula

in an alkaline milieu, in which R¹ has the meaning given above.

Formyl imidazoles are important intermediate products, for example, forthe production of pharmaceutical substances such as diuretics orantihypertensives (WO-A 92/20651). Several procedures have previouslybeen known for producing formyl imidazoles. In CH-A 685496, a procedureis described in which the catalytic oxidation of hydroxy methylimidazoles to formyl imidazoles is performed in the presence of noblemetal catalysts such as platinum/bismuth, platinum black, platinum orpalladium on activated charcoal, with oxygen insufflation.

The task of the invention was therefore to make available an economical,improved procedure for producing formyl imidazoles.

In this invention, this task is solved by the procedure defined in claim1. In claim 1, hydroxy methyl imidazoles of the general formula

in which R¹ has the meaning given above, are catalytically oxidized inan alkaline milieu in the presence of a noble metal catalyst and aperoxide to formyl imidazoles of the general formula

in which R¹ has the meaning given above.

R¹ has the meaning of hydrogen or an alkyl group, and more particularlya straight-chained or ramified alkyl group with 1 to 6 C atoms.Specifically, this may be methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert, butyl, pentyl and its isomers as well as hexyl and itsisomers. The preferred meaning of R¹ is butyl.

Hydroxy methyl imidazoles can be readily produced as starting compoundsas specified, for example, in WO-A 92/20651 or as in E. F. Godefroi etal., Trav. Chim. Recueil Pays Bas, 91, 1383 (1972).

Platinum, palladium, rhodium or gold may be used as the noble metalcatalyst. The noble metal is best used in combination with metals suchas, for example, bismuth, lead, cerium or indium as the secondcomponent. The preferred catalysts are platinum/bismuth orplatinum/lead.

The noble metal catalyst is used by itself or bound to a vehicle suchas, for example, activated charcoal, silicon dioxide, aluminum oxide,silicon-aluminum oxide, zirconium oxide or titanium oxide. It ispreferably bound to activated charcoal.

Noble metal catalysts bound to activated charcoal can be commerciallyobtained, for example, from Degussa.

The appropriate percentage of the noble metal bound to a vehicle isbetween 0.1 and 15% by weight, and preferably between 0.5 and 7% byweight, relative to the vehicle material.

The noble metal catalyst is preferably used in an amount of 0.05 to 1.0mol % noble metal base relative to the hydroxy methyl imidazole, and anamount of 0.1 to 0.4 mol % noble metal base relative to hydroxy methylimidazole is especially preferred.

Organic or inorganic peroxides are used as peroxides. Hydrogen peroxide,perborates, a percarboxylic acid, tert, butyl hydroperoxide, cumolhydroperoxide, perbenzoic acid, m-chloroperbenzoic acid, monoperphthalicacid or peracetic acid are well suited, for example. Hydrogen peroxideused in a 10% to 30% aqueous solution is particularly suitable.

In addition to the catalytic oxidation, the hydrolysis of the methylester of the hydroxymethyl imidazoles of general formula II takes placein an alkaline milieu.

The alkaline milieu is best obtained by the addition of an alkalihydroxide, an alkali carbonate or an alkali acetate to the reactionmixture. Alkali hydroxide is used preferably in a 1:0.05 to 5 ratio, andbest in a 1:3 ratio, relative to the mol amount used of thehydroxymethyl imidazole of general formula II.

The catalytic oxidation takes place best in an alkaline milieu in thepresence of water, a water-miscible solvent or mixtures thereof.

Particularly suitable water-miscibie solvents are, for example, alcoholsor carboxylic acids with 1 to 6 C atoms or ketones such as, for example,acetone or methyl ethyl ketone.

Mixtures of water and water-miscible solvents are preferably used.

The catalytic oxidation is best performed at a temperature of 20° to120° C., preferably at 50° to 100° C.

After the standard peroxide dosing time of 0.5 to 3 hours, the compoundof general formula I can be isolated in the standard manner after asufficient secondary reaction time.

The product is isolated by appropriate crystallization and filtration.The catalyst used can be used several times with no loss of activity.

EXAMPLES Example 1 Production of4-[(2-butyl-5-formyl-1H-imidazo-1-yl)methyl]benzoic acid

900 mg (3 mmol) of4-[(2-butyl-5-hydroxymethyl-1H-imidazo-1-yl)methyl]benzoic acid methylester, 8 ml caustic soda solution (1M), 0.5 ml methanol and 107 mgplatinum 5% and 5% bismuth on activated charcoal containing 60% waterare placed in a 25-ml flask at room temperature and heated to 60° C.

0.8 g (4.6 mmol) 20% aqueous H₂O₂ solution was added to this suspensionat 60° C. over 30 minutes and the mixture was then reacted with HPLC.Another 0.2 g (1.1 mmol) 20% aqueous H₂O₂ solution was then added over10 minutes. Then 0.2 g (5 mmol) 20% NaOH was added. The reactionsolution was heated for 2 hours at 100° C. The mixture was cooled toroom temperature. The catalyst was filtered over celite and washed with5 ml water. After acidification to pH 5.0 with HCl (15%), the productprecipitated out. It was cooled to 2° C., filtered, washed with 2×5 mlwater and dried at room temperature at 15 mbar. 410 mg (48%) yellow4-[(2-butyl-5-formyl-1H-imidazo-1-yl)methyl]benzoic acid were obtained(HPLC content 96%).

Melting point: 144-146° C.

¹H-NMR (DMSO-_(d6), 400 Mhz) δ:

12.9 (1H, s);

9.65 (1H, s);

7.94 (1H, s);

7.90 (2H, d);

7.11 (2H, d);

5.65 (2H, s);

2.63 (2H, t);

1.54 (2H, pent);

1.36 (2H, hex);

0.79 (3H, t).

What is claimed is:
 1. Procedure for producing formyl imidazoles of thegeneral formula

in which R¹ means an alkyl group, by catalytic oxidation of hydroxymethyl imidazoles of the general formula

in which R¹ has the meaning given above, in the presence of a noblemetal catalyst, characterized in that the catalytic oxidation takesplace in the presence of a peroxide in an alkaline milieu.
 2. Procedureas in claim 1, characterized in that R¹ is a butyl group.
 3. Procedureas in claim 1, characterized in that the noble metal catalyst is aplatinum/bismuth catalyst or a platinum/lead catalyst.
 4. Procedure asin claim 1, characterized in that the peroxide is hydrogen peroxide. 5.Procedure as in claim 1, characterized in that the alkaline milieu isobtained by adding an alkali hydroxide, an alkali carbonate or an alkaliacetate to the reaction mixture.
 6. Procedure as in claim 1,characterized in that the catalytic oxidation is performed in thepresence of water, a water-miscible solvent, or mixtures thereof, in analkaline milieu.
 7. Procedure as in claim 1, characterized in that thereaction is performed at a temperature of 20° to 120° C.